The self-administration of ethanol assessed under open-access conditions allows the characterization of how chronic ethanol intoxication pushes the organism beyond the normal limits of homeostasis (a constant internal environment) and into chronic, variable, stress responses (allostasis) and disease states. A critical barrier to understanding the apparent reciprocal relationship between stress and excessive ethanol drinking is the availability of within-subject comprehensive, longitudinal data sets on the neurogenetic, neurochemical, neurophysiological, neuroendocrine, and behavioral adaptations to chronic ethanol. The macaque monkey that self-administers high doses of ethanol for >20 months can provide these data sets; optimally within a highly collaborative and integrative environment such as the Integrative Neuroscience Initiative on Alcoholism (INIA). Therefore, in this renewal, we will continue to provide a nonhuman primate link in the INIA consortium to address fundamental aspects of what is known (or suspected) in humans with respect to stress, anxiety and excessive alcohol drinking. We propose to extend our study on longitudinal adaptations to excessive ethanol self-administration from cynomolgus monkeys to the rhesus monkey pedigree population at the Oregon National Primate Research Center (ONPRC). The studies will address fundamental questions of stress and risk for excessive drinking including consumption patterns following stressful provocations and repeated periods of prolonged abstinence from alcohol. Translational variables will include changes in the patterns of drinking alcohol as monkeys transition from moderate to heavy drinking, specific prefrontal cortical epigenetic adaptations, circulating endocrine and peptide markers, and functional connectivity MRI (fcMRl) studies. In addition, the research designs allow for unprecedented opportunities to investigate underlying synaptic changes in key regions of an integrative neural circuitry associated with the consequences of chronic alcohol self-intoxication. PUBLIC HEALTH RELEVANCE: Alcoholism is the third leading preventable cause of death in the U.S.A. At present, the role of stress in prompting some individuals to drink alcohol excessively is not known. Because monkeys, like humans, voluntarily drink to dependence and share 95% of our genetic makeup, they are excellent human surrogates to discover how stress regulates alcoholic drinking and thereby find more effective treatments for alcoholism.